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Pursuing Treatments for Biomarker-Driven Cancers and Rare Diseases
Jefferies 2019 Healthcare Conference on June 6, 2019
ArQule I
Forward Looking Statements
2
This presentation and other statements by ArQule contain forward-looking statements within the meaning of the Private Securities Litigation
Reform Act including, without limitation, statements with respect to current and proposed clinical trials with the Company’s product candidates
derazantinib (ARQ 087), miransertib (ARQ 092), ARQ 751 and ARQ 531, financial operations and results, potential corporate partnerships as
well as strategic objectives, business objectives, next steps, pipeline and other goals, clinical targets, projected inflection points, catalysts,
market estimates and potentials, opportunities and other strategies. Forward-looking statements are typically identified by words such as
“believe,” “expect,” “anticipate,” “intend,” “outlook,” “position,” “goal” and similar expressions, or future or conditional verbs such as “will,”
“should,” “would,” and “could.” Forward-looking statements are subject to numerous assumptions, risks and uncertainties. Forward-looking
statements speak only as of today, and ArQule assumes no obligation to update them. Actual results may differ materially from forward-
looking statements or historical performance due to the factors discussed in this presentation and factors previously disclosed in ArQule’s
SEC reports. See discussion of Risk Factors in the Company’s Annual Report on Form 10-K as filed with the SEC. Prospective investors are
cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this presentation. ArQule’s
product candidates are in various stages of development and are not available for sale or use outside of approved clinical trials.
ArQule and the ArQule logo are registered trademarks of ArQule, Inc.
ArQule I 3
Experienced Developer of Novel Kinase Inhibitors
Four Novel Oral Compounds in Clinical Development
Biomarker-driven discovery of precision medicines for cancer and rare diseases
with potential for accelerated registration paths
01
02
03
04
Reversible BTK inhibitor, ARQ 531, that can overcome ibrutinib resistance – wholly owned
AKT inhibitor, miransertib, in registrational trial for certain rare overgrowth diseases – wholly owned
FGFR inhibitor, derazantinib, in a registrational trial for intrahepatic cholangiocarcinoma – globally partnered
Next-Gen AKT inhibitor, ARQ 751, for solid tumors –wholly owned
ArQule I
Class Indication Current StageTarget for
Next StageMarket Potential
(est.)
ARQ 531Reversible BTK inhibitor
B-cell malignancies Phase 1a/bPhase 2 Expansion /
Registrational
Large (and growing) blockbuster market potential
MIR
AN
SE
RT
IB RARE DISEASES
AKT inhibitorProteus Syndrome
PROS
Registrational Cohorts
Orphan Designation
Rare Ped. Dis. Des. (PS)
Fast Track Des. (PROS)
NDA Filing
Meaningful aggregate prevalence
Rare Pediatric Disease voucher, if approved
ONCOLOGYAKT inhibitor
Solid tumors / AKT pathway mutations
Phase 1bContinue or transition to ARQ 751
Blockbuster potential in hormone sensitive tumors
ARQ 751Next generation AKT inhibitor
Solid tumors / AKT pathway mutations
Phase 1b Phase 2 Blockbuster potential
in hormone sensitive tumors
DERAZANTINIB FGFR inhibitoriCCA (Intrahepatic cholangiocarcinoma)
Registrational Orphan Designation
NDA Filing
Partnered – up to $400MM in regulatory and sales milestones plus royalties
Summary of Programs and Pipeline Goals
4
ArQule I
ArQule’s Proprietary Pipeline
5
Product MOA Indication Rights IP1 Key 2019 Catalysts Pre-clinical Phase 1 Phase 2Phase 3 /
Registrational
ARQ 531Reversible BTK Inhibitor
B-cell Malignancies 2035
Final dose selection Commence enrollment of
expansion cohorts Plan registrational trial in C481S
mutated CLL patients (2H19)
Miransertib
AKT InhibitorPROS & Proteus syndrome
2032 Commence registrational cohorts
in both Proteus syndrome and PROS (1H19)
AKT InhibitorSolid tumors / AKT pathway mutations
2032 Present data from Phase 1b
cohorts (2H19)
ARQ 751 AKT InhibitorSolid tumors / AKT pathway mutations
2032
Present data from Phase 1b cohorts (2H19)
Prioritize for further development (2H19)
DerazantinibFGFR Inhibitor
Intrahepatic cholangiocarcinoma (iCCA)
2031
Basilea to pursue expanded development strategy
Sinovant to initiate program in Greater China (1H19)
1. Composition of Matter only, does not include possible extensions2. U.S., EU, Japan and ROW3. China, Hong Kong, Macau and Taiwan
2
3
ARQ 531 Reversible BTK inhibitor in B-cell
malignancies
6
ArQule I
B-CELL MALIGNANCIESCURRENT THERAPY
& UNMET NEEDARQ 531 MARKET VALUE
B-Cell malignancies are a diverse group of diseases, including chronic lymphocytic leukemia (CLL), most non-Hodgkin’s lymphomas, other leukemias and myelomas
BTK is an ubiquitous component of the B-cell receptor (BCR) pathway
BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion
Ibrutinib and acalabrutinib are irreversible BTK inhibitors that covalently bind the catalytic site
Long term treatment with approved BTK inhibitors can leadto mutations, most notably C481S, which leads to resistance
Reversible small molecule next generation BTK inhibitor targeting both WT and C481S-mutant BTK
Potent, orally administered, with predictable PK
Currently in phase 1 trial for B-cell malignancies
Unique kinase profile, inhibits selected members of Tec, Src and Trk families
More than 20,000 patients diagnosed with CLL in the US in 20171
~85% of CLL patients refractory to ibrutinib develop the C481S mutation2
Potential to move into earlier lines of therapy and indications beyond CLL
Potential blockbuster market in CLL alone
Targeting BTK in B-cell Malignancies
71 https://seer.cancer.gov/statfacts/html/clyl.html
2 Woyach J et al. “BTK(C481S)-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia”. J Clin Oncol. 2017 May 1;35(13):1437-1443
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ARQ 531 Addresses Treatment Resistance via Differentiated Binding Characteristics1
8
1.1 Ångstrom resolution crystal structureof ARQ 531 with BTK
Binding mode of ibrutinib with BTK
HEK293T cells
1Reiff SD, Byrd J, Woyach J et al. “The BTK Inhibitor ARQ 531 Targets Ibrutinib Resistant CLL and Richter's Transformation.” Cancer Discov, August 9 2018 DOI: 10.1158/2159-8290.CD-17-1409
ARQ 531
C481
Ibrutinib
Irreversible BTK inhibitors, such as ibrutinib, covalently bind to cysteine in position 481. A
cysteine to serine mutation (C481S) prevents this interaction
ARQ 531 was specifically designed to inhibit BTK regardless of the amino acid
position in position 481
Covalent interaction requires
cysteine in position 481
No interaction
with or requirement for cysteine in position
481
As a result, both inhibit WT BTK, but ARQ 531 also inhibits
C481S BTK
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ARQ 531 Demonstrates Compelling Activity in CLL in vitro and in vivo1
9
0
10
20
30
40
50
60
Vehicle Ibrutinib (25mg/kg)
ARQ 531(50 mg/kg)
ARQ 531(75 mg/kg)
Media
n S
urv
ival (d
)
Median Survival of Mice
Dose dependent cytotoxicityto CLL cells in vitro at 48h
Superior survival vs ibrutinib in TCL1, a highly predictive murine model of CLL
NotReached
NotReached
Comparative Survival Curves
1Reiff SD, Byrd J, Woyach J et al. “The BTK Inhibitor ARQ 531 Targets Ibrutinib Resistant CLL and Richter's Transformation.” Cancer Discov, August 9 2018 DOI: 10.1158/2159-8290.CD-17-1409
ArQule I 10
Ongoing Phase 1 Dose Escalation in Refractory B-cell Malignancies
Dose Escalation ParadigmPhase 1 Trial
Primary Objectives: Establish safety and tolerability of ARQ 531 and recommended phase 2 dose (RP2D)
Secondary Objectives: Preliminary evidence of anti-tumor activity, PK/PD measures
Location: 3+ sites in US with the Ohio State University as the lead
Design: 3+3 dose escalation
Enrollment: 30-50 B-cell malignancy patients refractory to any B-cell therapy, including but not limited to ibrutinib
Target Population:
Patients with relapsed and refractory (R/R) CLL o Must have failed irreversible BTK inhibitoro Median lines of therapy: 5.5 (1-12)
Other patients with R/R non-Hodgkin’s lymphoma
o DLCBL, MCL, WM, FL
ClinicalTrials.gov Identifier: NCT03162536
Expansion at RP2D
Cohort 1: 5 mg QD
Cohort 2: 10 mg QD
Cohort 3: 15 mg QD
Cohort 4: 20 mg QD
Cohort 5: 30 mg QD
Cohort 6: 45 mg QD
Cohort 7: 65 mg QD
Cohort 8: 75 mg QD Current
Cohort cleared for safety and intra-patient dose escalation
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Predictable PK Into the Clinically Relevant RangesHighly Favorable Safety Profile to Date
Interim Phase 1 Data from ASH 2018 Demonstrates Good Safety Profile and Favorable Drug-Like Properties. . . 1
11
Tre
atm
en
t E
merg
en
t A
dvers
e E
ven
ts
1Woyach J et al, ASH Annual Meeting 2018
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BTK activity/signaling correlated with substantial reductions after only 1 scan, despite failing multiple prior therapies
BTK activity/signaling profoundly suppressed at predicted doses/concentrations
-60
-40
-20
0
20
40
60
80
100
7 20 4 14 1
% S
PD
change
. . . As Well as Profound Pharmacodynamic Effects and Promising Anti-Tumor Activity1
12
Low dose range cohorts (1-3) showed an average 50% inhibition
Profound pBTK reductions were achieved at ≥ 20 mg dose levels
However, one patient in the 1st cohort (5 mg) achieved complete pBTKreduction, was later dose-escalated and achieved a confirmed partial
response
CV: Variability of pBTK/BTK ratio determination in the validated whole blood assay was ~±15%
pBTK Inhibition vs Cmax of ARQ 531 by Cohort
Best Responses in Lymphoma (BTK inhibitor naïve)
Durable partial response was observed in one of three
patients with FL
Best Responses in CLL(Heavily pretreated: median 6 therapies)
Anti-tumor activity was observed in heavily pretreated CLL patients with BTK-C481S
mutations with increasing tumor suppression seen at higher dose levels
1Woyach J. et al, ASH Annual Meeting 2018
1 2 3 4 5 60
20
40
60
80
100
120
% p
BT
K In
hib
itio
n
pBTK inhibition by Cohort
Cohort
(5mg) (10mg) (15mg) (20mg) (30mg) (45mg)
0
20
40
60
80
100
120
0 200 400 600 800
Mea
n %
pB
TK in
hib
itio
n
Cmax, nM
Cohort 6Cohort 5Cohort 4
Cohort 3
Cohort 2
Cohort 1
CV
DLBCLDLBCLFLFL
+
10 mg
45 mg
10 mg
15 mg
45 mg
-50
-30
-10
10
30
50
70
15 5 2 3 8 11 16 13 18 12 19 23 22
% S
PD
ch
an
ge
+++++ +
5 mg10 mg15 mg20 mg30 mg45 mg
+ On study
Patient ID
Patient ID
FL
ArQule I
Expansion at RP2D
Phase1b Open Label, Multicenter, Study of ARQ 531 in Patients with R/R B-cell Malignancies
13
Key Objectives: To determine safety, tolerability and anti-cancer activity
Dose Level: Recommended dose based on phase 1a
Enrollment: An additional 80-100 patients; multiple cohorts (i.e., CLL patients with C481S-mutant BTK)
BTK C481Smutant
Richter’s syndrome
DLBCL
FL
CNS Lymphoma
MCL
WM
CLL
NHL
14
MIRANSERTIB AKT inhibitor in Rare Overgrowth
Spectrum Disorders
ArQule I
OVERGROWTH DISEASES
CURRENT THERAPY& UNMET NEED
MIRANSERTIB MARKET VALUE
Group of diseases characterized by excessive aberrant, asymmetric growth of bones, skin and other tissues
Manifests in early childhood
Proteus syndrome caused by mosaic mutation in AKT1 gene
PROS family of diseases caused by mosaic mutation in PIK3CA gene
No approved systemic treatments for PROS or Proteus syndrome; current Rx relies on expensive and disfiguring surgical amputations
Proteus syndrome: estimated 200-400 patients in the US and Europe1
PROS: estimated 3000 – 6000 patients in US and Europe1
Small molecule pan-AKT inhibitor
Potent, orally administered with predictable PK
Differentiated mechanism of action relative to other AKT inhibitors
Registrational trial cohorts in PS and PROS ready to commence
Meaningful aggregate prevalence across overgrowth spectrum disorders
Rare pediatric disease voucher for PS, if approved
Additional market value outside of US/EU, and in additional indications1
Targeting AKT in Rare Overgrowth Diseases1
151. See presentation “PS & PROS Primer 2019” at arqule.com
ArQule I
Miransertib Crystal Structure and Mechanism of Action
16
Dual mechanism of action:
Binds inactive AKT and prevents membrane localization and activation
Binds membrane associated active AKT: direct inhibition
First generation pan-AKT inhibitor
Potent, orally active, small molecule allosteric inhibitor of AKT
Adapted from www.cbioportal.org
01
02
ArQule I
A Mutation in AKT1 Causes Proteus Syndrome
17
Somatic mosaic mutation in the AKT1 oncogene causes Proteus syndrome (PS)
Non-inherited mutation arises randomly during early stages of development before birth
Single point mutation in AKT1 gene causes tissue overgrowth characteristic of PS
Mortality of 25% by age 22
Currently no approved treatments
Clinical Manifestations of the Proteus syndrome in a 12-Year-Old Boy.
A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome
Identification of underlying mutation allows for development of molecularly targeted treatments
Marjorie J. Lindhurst, Julie C. Sapp, Jamie K. Teer…Leslie G. Biesecker
ArQule I
PROS: A Related Group of Severe Overgrowth Disorders
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PIK3CA-related overgrowth spectrum (PROS) is a group of rare disorders that cause overgrowth of parts of the body due to gain of function mutations in PIK3CA gene
Congential or early onset
Disorders include:
o CLOVES syndrome
o Klippel-Trénaunay syndrome (KTS)
o Megalencephalies (includes MCAP, MPPH, M-CMTC, etc)
o Facial Infiltrating Lipomatosis (FIL)
o Fibroadipose hyperplasia (FH)
o Epidermal Nevi
o Macrodactyly
o Macrodystrophica Lipomatosa
o . . . and many others
Varying degree of severity, with some tissue specific and others pleiotropic
Currently no pharmacotherapy options
Multiple surgical interventions including debulking, amputation and corrective surgery
Patients may suffer from severe functional and cosmetic consequences and progress to becoming poor surgical candidates
Valentini V et al. (2018). Clin Case Rep.Gripp KW et al. (2016). Am J Med Genet ASuzuki Y et al. (2017). OncotargetYatong Y et al. (2018). Ann Plast Surg; 80: 83-89
ArQule I
Rapid Path to Approval in Both PS and PROS
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Registrational Cohort in PS, N~ 10-12 pts
Registrational Cohort in PROS, N~ 20-24 pts
NDA Filing PS Approval
NDA Filing PROS Approval
RPD Voucher
Design: Open Label
Primary Endpoint: Responder analysis, based on objective criteria (e.g. imaging measurements)
Enrollment: 10-12 months
Time on drug: 12 months to primary endpoint
Dosing: 15 mg/m2 for first 3 cycles, 25 mg/m2 thereafter
Signal Generation Cohort: PS or PROS patients who did not qualify for cohorts 1 or 2
Ph1/2 trial data Comp. use data FDA Interactions
Signal Generation Cohort
20
MIRANSERTIB & ARQ 751 Targeted AKT inhibitors in oncology
ArQule I
CURRENT THERAPY & UNMET NEED
MIRANSERTIB ARQ 751 MARKET VALUE
Currently no approved AKT inhibitors
AKT inhibitors in development, either single agent or in combination, show promise in a molecular defined patient population, e.g., breast, prostate and endometrial cancer
Small molecule pan-AKT inhibitor
Potent, orally administered with predictable PK
Differentiated mechanism of action relative to other AKT inhibitors
Binds to the inactive form of AKT preventing membrane localization and activation as well as binding to active form of AKT with direct inhibition
Orally administered, next generation small molecule AKT inhibitor with predictable PK
Designed to be more potent and selective than miransertib with a wider therapeutic index
3-5% of solid tumors have mutations in the AKT pathway1
PIK3CA mutations present in 32% colon, 27% brain, 25% gastric tumors, 37% endometrial, 31% breast and 2-3% prostate cancers2,3,4
PTEN loss or mutation in up to 59% of stage IV cancers5
Targeting AKT in Oncology
211Yi, KH and Lauring, J, Oncotarget, 7(4): 4241-4251, 2016; 2Millis SZ et.al. JAMA Oncol. 2016;2(12):1565-1573; 3Samuels, Y et al. Science, 304(5670):554, 2004; 4Sun,X et al. Anticancer
Research, 2009;5(29):1739-1743; 5Alfieri R. Giovannetti E, et al. Frontiers in Oncology, 7(710), 2017
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ARQ 751 Trial Design & Next Steps
22
Phase 1a/b trial in solid tumors with AKT, PI3K and PTEN mutations
Phase 1a/1b Trial Phase 2 Trial
Key Objectives: Establish safety of ARQ 751, PK/PD measures, recommended phase 2 dose and preliminary efficacy
Location: MD Anderson Cancer Center, Houston TX
Design: open-label, single group assignment dose escalation study
Enrollment: 100 patients
Target Population: Patients with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations, PTEN-null or other known actionable PTEN mutations
ClinicalTrials.gov Identifier: NCT02761694
Key Objectives: Efficacy of ARQ 751
Dose Level: Recommended phase 2 dose
Enrollment: Molecularly defined patient population
Next Steps
Present data from phase 1b cohorts (2H19)
Initiate additional trial if supported by phase 1b data (2H19)
ArQule I
ArQule (NASDAQ: ARQL) Financial Profile
23
Common Stock O/Sas of December 31, 2018
109M
Market Capas of March 8, 2019
$554M
2019 Expected Use of Cash $35-40M
Projected Cash & Marketable Securities*at December 31, 2019
$60-63M
*Sufficient cash to fund operating expenses into 2021
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